+

WO1996004015A1 - Preparations de microparticules pour l'elimination de substances dissoutes dans le sang - Google Patents

Preparations de microparticules pour l'elimination de substances dissoutes dans le sang Download PDF

Info

Publication number
WO1996004015A1
WO1996004015A1 PCT/EP1995/002886 EP9502886W WO9604015A1 WO 1996004015 A1 WO1996004015 A1 WO 1996004015A1 EP 9502886 W EP9502886 W EP 9502886W WO 9604015 A1 WO9604015 A1 WO 9604015A1
Authority
WO
WIPO (PCT)
Prior art keywords
preparations according
microparticle preparations
microparticle
antibodies
biopolymer
Prior art date
Application number
PCT/EP1995/002886
Other languages
German (de)
English (en)
Inventor
Werner Weitschies
Dieter Heldmann
Thomas Bunte
Ulrich Speck
Original Assignee
Schering Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to AU31638/95A priority Critical patent/AU3163895A/en
Publication of WO1996004015A1 publication Critical patent/WO1996004015A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/44—Antibodies bound to carriers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface

Definitions

  • the invention relates to the subject characterized in the claims, that is to say the use of microparticle preparations for the elimination of non-renal substances from the blood.
  • immunoscintigraphy is a radioactively labeled structure-specific antibody that is directed against certain tumors, for example. Only a small part of the injected labeled antibodies binds to the desired structure and / or location in the body tissue, the rest remains in the bloodstream and causes a strong one Background noise (blood contrast), which makes detection of specific accumulation, for example in tumor tissue, very difficult or impossible.
  • EP 0 251 494 describes a system for eliminating the antibodies circulating in the blood with proteins.
  • the method disclosed in this patent has the disadvantage that the proteins used there have to meet very specific requirements with regard to their size.
  • Another disadvantage is that the proteins used there are in most cases not recognized as "foreign" by the body and are therefore only slowly absorbed into the MPS after they have formed a corresponding conjugate with the antibody to be removed.
  • the object of the present invention was therefore to develop a system by means of which MPS can be used to rapidly remove antigen-antibody conjugates or other conjugates from the blood circulation (hereinafter referred to as "blood clearance").
  • microparticle preparations are excellently suited for the elimination of dissolved, non-renal substances from the blood.
  • Suitable for "blood clearence” are in particular microparticle preparations made from biopolymers, from biodegradable copolymers which are composed of a synthetic polymer and a biopolymer or from lipids which are attached to the
  • Particle surface have structure-specific substances that are capable of in a ligand-receptor bond with non-kidney-accessible substances dissolved in blood to form a particulate aggregate which is excreted via the cells of the patient's mononuclear phagocytic system (MPS).
  • MPS mononuclear phagocytic system
  • microparticle preparations also includes liposomes.
  • Microparticle preparations consisting of:
  • a structure-specific compound is bound via functional groups or linkers or e)
  • a bio- or macromolecule with structure-specific properties is bound from a synthetic polymer via the functional groups thereof - optionally via a linker.
  • Capillary-accessible microparticle preparations with a particle diameter of 0.1-6 ⁇ m can preferably be used according to the invention.
  • Microparticle preparations as described in DE 42 32 755, EP 0 441 468 and WO 91/00289 are particularly suitable.
  • microparticle preparations of DE 42 32 755 which can be used according to the invention consist of a copolymer made of at least one synthetic polymeric material and at least one biopolymer which has structure-specific properties or functional groups via which structure-specific substances are bound.
  • biodegradable polymer that is composed of (a) polymerizable aldehyde (s) - if desired, additives and / or suitable for copolymerization Crosslinkers - and coupling agents via which bio- or macromolecules (which have structure-specific properties) are bound.
  • Liposomes which can be used according to the invention are described in WO 91/00289. There, inter alia, liposomes produced from phosphatidylethanol (PE) and maleimido and amino group-containing "cross-linkers” (such as SMPB) are disclosed which are covalently linked to proteins (e.g. antibodies, IgG, hapten).
  • PE phosphatidylethanol
  • cross-linkers such as SMPB
  • microparticle preparation from a biopolymer with structure-specific properties e.g. Particles from collagan (antigen) called, which were coupled for example by glutaraldehyde (see Example 2).
  • Particles from collagan (antigen) called which were coupled for example by glutaraldehyde (see Example 2).
  • Such particles can be used according to the invention for blood clearance.
  • the desired substances e.g. antigens, proteins / peptide antibodies, haptens, biotin, digoxigenin
  • the coupling can also be carried out via bifunctional reagents (so-called linkers) such as N-succinimidyl-3- (2-pyridyldithiol) (SPDP) or m-maleimidazonizoyl-N-hydroxysuccinipide (MBS).
  • linkers such as N-succinimidyl-3- (2-pyridyldithiol) (SPDP) or m-maleimidazonizoyl-N-hydroxysuccinipide (MBS).
  • the biopolymers can also be part of a copolymer which, in addition to the biopolymer, also contains a synthetic polymer [point d)].
  • the specificity of the corresponding microparticle preparation is essentially determined by the biopolymer, or by structure-specific substances linked to the functional groups of the biomolecule, if necessary via linker molecules.
  • the synthetic polymer essentially serves to stabilize the microparticles, especially in cases where the biopolymer per se is not suitable for forming microparticles which are stable in vivo over a sufficiently long period of time.
  • Synthetic polymers which are preferably used are polyesters of ⁇ -, ⁇ -, ⁇ - or ⁇ -hydroxycarboxylic acids, polyalkylcyanoacrylates, polyamic acids, polyamides, polyacrylated saccharides or poly (ortho) esters (DE 38 03 972) or polyphosphazenes (US 5,149,543).
  • Polymers composed of acrylic acid, acrylamide, acrylic acid chloride or acrylic acid glycide ester are also suitable. If the synthetic polymer is made up of polymerizable aldehydes, ⁇ -, ⁇ -unsaturated aldehydes such as acrolein or crotonaldehyde are particularly suitable (EP 0 441 468).
  • Preferred coupling agents (linkers) are bifunctional compounds containing amino groups, e.g. Amino acids, hydroxylamine or hydrazine in question.
  • the polyaldehydes can also be crosslinked, e.g. Dialdehydes such as glutardialdehyde can be crosslinked.
  • the preferred biopolymers are glycosylated and non-glycosylated polypeptides or proteins as well as biopolymers to which - via the functional groups of the biopolymer - site, structure and / or tissue-specific substances are bound (DE 42 32 755).
  • the binding of the substances that are dissolved in the blood and cannot be eliminated by the kidneys to the microparticle preparations can be achieved in different ways. What they all have in common is that they are based on the basic principle of ligand-receptor binding (as explained in more detail below).
  • non-renal substance is understood to mean substances which are normally not excreted efficiently via the kidney, that is to say in patients who are not kidney-deficient. Such substances include molecules and their constituents with a molecular weight greater than 30,000 Daltons, but also endogenous substances that are absorbed from the kidney, e.g. endogenous acids such as Uric acid.
  • Structural (site and / or tissue) -specific substances are understood to mean substances which react in a ligand-receptor bond with the substance to be eliminated, the term "ligand-receptor binding” meaning the specific binding of two molecules is to be understood among each other, in the simplified description that one works analogously to a "key” and the other analogously to a “lock” (key-lock principle).
  • Systems in which the binding constant of the “ligand-receptor binding” is in the range from 10 7 to 10 15 (mol / 1) - 1 can be used in accordance with the invention. Table 1 below shows the various possibilities that exist for binding the substances to be eliminated dissolved in the blood to microparticle preparations (in a ligand-receptor bond).
  • Microparticle to be eliminated substance dissolved in blood binding type contains antigen X antibody or antibody antigen-antibody fragment against antigen X binding contains avidin is coupled with biotin avidin-biotin binding contains biotin is coupled with avidin contains avidin-biotin binding Antibody Y Antigen from Antibody Y Antigen-Antibody Binding
  • the microparticle preparations can thus carry the antigen of the dissolved antibody to be eliminated from the blood on their surface.
  • An example is collagen type 3 as an antigen in antibodies directed against type 3 collagen as a dissolved substance to be eliminated in the blood (see example 3).
  • Streptavidin / biotin which has a high binding constant [10 15 (mol / 1) -1 ] or the digoxigenin / antibody system against digoxigenin, which has a lower binding constant than the aforementioned system, but has other advantages over biotin, such as alleviating the problems of
  • FIG. 2 shows schematically the different possibilities of blood purification of circulating antibodies by means of particulate systems.
  • microparticle preparations according to the invention in the field of immunoscintigraphy also gives rise to further advantages.
  • the time interval between the injection of the radioactively labeled antibodies and their detection can be considerably shortened by the use of microparticle preparations according to the invention in "blood clearance”.
  • images that have a high diagnostic value can be obtained after 1-3 hours by injecting microparticle preparations (see also FIG. 3).
  • the drastic shortening of the residence time of the radioactively labeled compound has an especially advantageous effect in positron emission tomography (PET), since the diagnostic use of this method frequently failed due to the long residence times of the labeled compounds in the blood.
  • PET positron emission tomography
  • microparticle preparations according to the invention can also be used advantageously in therapeutic processes, for example when removing substances which have entered the body from the outside from the blood (blood clearance).
  • blood clearance for example, in the case of hemolyticus neonatorum before birth, the antibody titers of the mother against the rhesus positive antigen on the erythrocytes of the child can be reduced by administration of antigen-carrying microparticles.
  • the microparticle suspension can optionally be injected directly into the infant.
  • Antibodies are removed by microparticle preparations that carry this antigen].
  • the antigens found in the body can be removed from the blood with microparticle preparations that contain the corresponding antibody].
  • microparticle preparations can be used in the blood purification of autoimmune diseases, for example In Myaesthenia gravis the antibodies against the acethylcholine receptor with microparticles containing this antigen (receptor),
  • the anti-inflammatory anti-human IgG antibodies with microparticles which contain the corresponding antigen In rheumatoid arthritis, the anti-inflammatory anti-human IgG antibodies with microparticles which contain the corresponding antigen,
  • microparticle preparations are injected intravenously, and the agent can be administered as a "bolus” or as an "infusion".
  • the amount of microparticle preparations to be used depends on a) the number of binding sites in the microparticle preparation and b) the respective amount of the antibody to be removed from the blood (antibody titer). This "titer" is either - as in the case of immunoscintigraphic
  • microparticle preparations are then used in a molar ratio of 1: 1 to 1:20 based on the available binding sites.
  • concentration of the microparticle preparations is usually 5 x 10 O 11
  • compositions per ml of suspension medium.
  • Pharmaceutically acceptable media such as e.g. Water p.L, aqueous solutions of one or more inorganic salts such as physiological electrolyte solutions, aqueous solutions of mono- or disaccharides such as glucose or lactose, sugar alcohols such as mannitol, but preferably water for injections, use.
  • the total concentration of any dissolved substances is 0-20 percent by weight.
  • microparticles are then separated by centrifugation (5000 rpm, 10 minutes) and washed by centrifugation 5 times with a mixture of 75% toluene and 25% methylene chloride, 5 times with isopropyl alcohol and 5 times with isotonic saline. After the last centrifugation, the microparticles are taken up in 5 ml of isotonic saline and filtered through a filter with a pore size of 5 ⁇ m.
  • Two rats each received an IV injection of a 125 I-labeled antibody against type 3 collagen (4.4 x 10 6 cpm / dose). After reaching the blood level plateau (3 hours after injection), a dose of 2 ⁇ 10 7 particles coupled with type 3 collagen (produced according to Example 1) is injected into the tail vein in rat 1.
  • Rat 2 is injected at the same time with 2 ⁇ 10 8 collagen-free particles (produced according to Example 1 without coupling with type 3 collagen). After these injections, a clear decrease in the antibody blood level can be seen in rat 1 within 15 minutes (cf. FIG. 3), while in rat 2 no change in the antibody blood gel by particle administration is achieved (cf. FIG. 4).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dispersion Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne l'utilisation de préparations de microparticules pour l'élimination, dans le sang, de substances non éliminées au niveau des reins.
PCT/EP1995/002886 1994-07-29 1995-07-21 Preparations de microparticules pour l'elimination de substances dissoutes dans le sang WO1996004015A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU31638/95A AU3163895A (en) 1994-07-29 1995-07-21 Microparticle preparations for clearing blood-dissolved substances

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4428056A DE4428056A1 (de) 1994-07-29 1994-07-29 Verwendung von Mikropartikelpräparationen zur Eliminierung gelöster, nicht nierengängiger Substanzen aus dem Blut
DEP4428056.4 1994-07-29

Publications (1)

Publication Number Publication Date
WO1996004015A1 true WO1996004015A1 (fr) 1996-02-15

Family

ID=6525199

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/002886 WO1996004015A1 (fr) 1994-07-29 1995-07-21 Preparations de microparticules pour l'elimination de substances dissoutes dans le sang

Country Status (5)

Country Link
AU (1) AU3163895A (fr)
DE (1) DE4428056A1 (fr)
IL (1) IL114712A0 (fr)
WO (1) WO1996004015A1 (fr)
ZA (1) ZA956330B (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999016477A3 (fr) * 1997-09-30 1999-06-17 Univ Heidelberg 32p-polyphosphazene
US7265199B2 (en) 2000-04-11 2007-09-04 Celonova Biosciences Germany Gmbh Poly-tri-fluoro-ethoxypolyphosphazene coverings and films
US7922764B2 (en) 2006-10-10 2011-04-12 Celonova Bioscience, Inc. Bioprosthetic heart valve with polyphosphazene
US8007821B2 (en) 2001-01-11 2011-08-30 Celonova Biosciences Germany Gmbh Substrates containing polyphosphazene as matrices and substrates containing polyphosphazene with microstructured surface
US8101275B2 (en) 2001-08-17 2012-01-24 Celonova Biosciences, Inc. Device based on nitinol, a process for its production, and its use
US9080146B2 (en) 2001-01-11 2015-07-14 Celonova Biosciences, Inc. Substrates containing polyphosphazene as matrices and substrates containing polyphosphazene with a micro-structured surface
US9107850B2 (en) 2004-10-25 2015-08-18 Celonova Biosciences, Inc. Color-coded and sized loadable polymeric particles for therapeutic and/or diagnostic applications and methods of preparing and using the same
US9114162B2 (en) 2004-10-25 2015-08-25 Celonova Biosciences, Inc. Loadable polymeric particles for enhanced imaging in clinical applications and methods of preparing and using the same
US10973770B2 (en) 2004-10-25 2021-04-13 Varian Medical Systems, Inc. Color-coded and sized loadable polymeric particles for therapeutic and/or diagnostic applications and methods of preparing and using the same

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986004232A1 (fr) * 1985-01-18 1986-07-31 Cooper-Lipotech, Inc. Composition liposomique
EP0251494A2 (fr) * 1986-06-23 1988-01-07 The Board Of Trustees Of The Leland Stanford Junior University Composé thérapeutique ou radiodiagnostique
WO1991018020A1 (fr) * 1990-05-17 1991-11-28 Albany Medical College Complexe utilise pour la localisation in-vivo de cibles
WO1995021628A1 (fr) * 1994-02-14 1995-08-17 Synsorb Biotech Inc. Traitement de la diarrhee associee a la prise d'antibiotiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986004232A1 (fr) * 1985-01-18 1986-07-31 Cooper-Lipotech, Inc. Composition liposomique
EP0251494A2 (fr) * 1986-06-23 1988-01-07 The Board Of Trustees Of The Leland Stanford Junior University Composé thérapeutique ou radiodiagnostique
WO1991018020A1 (fr) * 1990-05-17 1991-11-28 Albany Medical College Complexe utilise pour la localisation in-vivo de cibles
WO1995021628A1 (fr) * 1994-02-14 1995-08-17 Synsorb Biotech Inc. Traitement de la diarrhee associee a la prise d'antibiotiques

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DATABASE EMBASE ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL; *
DATABASE MEDLINE US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; *
JULIANO R. L.: "FACTORS AFFECTING THE CLEARANCE KINETICS AND TISSUE DISTRIBUTION OF LIPOSOMES, MICROPSHERES AND EMULSIONS.", ADV. DRUG DELIV. REV., vol. 2, no. 1, pages 31 - 54, XP023844320, DOI: doi:10.1016/0169-409X(88)90004-X *
KEIDING S.: "ENHANCEMENT OF UNBOUND OF IGC BY PLASMA PROTEINS, DEMONSTRATED IN HUMAN SUBJECTS AND INTERPRETED WITHOUT ASSUMPTION OF FACILATING STRUCTURES.", J. HEPATOL., vol. 19, no. 3, pages 327 - 344 *
WANG H T ET AL: "INFLUENCE OF FORMULATION METHODS ON THE IN VITRO CONTROLLED RELEASE OF PROTEIN FROM POLY (ESTER) MICROSPHERES", JOURNAL OF CONTROLLED RELEASE, vol. 17, no. 1, 1 September 1991 (1991-09-01), pages 23 - 31, XP000223264 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999016477A3 (fr) * 1997-09-30 1999-06-17 Univ Heidelberg 32p-polyphosphazene
US7265199B2 (en) 2000-04-11 2007-09-04 Celonova Biosciences Germany Gmbh Poly-tri-fluoro-ethoxypolyphosphazene coverings and films
US8007821B2 (en) 2001-01-11 2011-08-30 Celonova Biosciences Germany Gmbh Substrates containing polyphosphazene as matrices and substrates containing polyphosphazene with microstructured surface
US9080146B2 (en) 2001-01-11 2015-07-14 Celonova Biosciences, Inc. Substrates containing polyphosphazene as matrices and substrates containing polyphosphazene with a micro-structured surface
US8101275B2 (en) 2001-08-17 2012-01-24 Celonova Biosciences, Inc. Device based on nitinol, a process for its production, and its use
US9107850B2 (en) 2004-10-25 2015-08-18 Celonova Biosciences, Inc. Color-coded and sized loadable polymeric particles for therapeutic and/or diagnostic applications and methods of preparing and using the same
US9114162B2 (en) 2004-10-25 2015-08-25 Celonova Biosciences, Inc. Loadable polymeric particles for enhanced imaging in clinical applications and methods of preparing and using the same
US9597419B2 (en) 2004-10-25 2017-03-21 Boston Scientific Limited Loadable polymeric particles for enhanced imaging in clinical applications and methods of preparing and using the same
US10973770B2 (en) 2004-10-25 2021-04-13 Varian Medical Systems, Inc. Color-coded and sized loadable polymeric particles for therapeutic and/or diagnostic applications and methods of preparing and using the same
US7922764B2 (en) 2006-10-10 2011-04-12 Celonova Bioscience, Inc. Bioprosthetic heart valve with polyphosphazene

Also Published As

Publication number Publication date
DE4428056A1 (de) 1996-02-08
ZA956330B (en) 1996-06-04
IL114712A0 (en) 1995-11-27
AU3163895A (en) 1996-03-04

Similar Documents

Publication Publication Date Title
DE69228802T2 (de) System zur verbesserten in-vivo aussonderung diagnostischer und/oder therapeutischer wirkstoffe durch extrakorporales entfernen der wirkstoffe
DE3885461T2 (de) Biospezifische polymere.
EP0186616B1 (fr) Particules magnétiques comme agent diagnostique
DE3587477T2 (de) Verfahren zur radioaktiven Markierung von diagnostischen und therapeutischen Agenzien die eine Chelatierungsgruppe enthalten.
DE69034042T2 (de) System zur verwendung in einem verfahren zur therapeutischen und diagnostischen behandlung
DE2202441C3 (fr)
DE2902400A1 (de) Verbesserter, spezifischer doppelrezeptor-bindetest fuer einen probenliganden
DE3752007T2 (de) Mittel zur Entziehung von Endprodukten der fortgeschrittenen Glycosylation
DE112005001901T5 (de) Einfangen und entfernen von Biomolekülen aus Körperflüssigkeiten unter Verwendung von partiellen molekularen Abdrücken
DE10121982A1 (de) Nanopartikel aus Protein mit gekoppeltem Apolipoprotein E zur Überwindung der Blut-Hirn-Schranke und Verfahren zu ihrer Herstellung
DE3443251C2 (de) Eisenoxid-Komplexe für die NMR-Diagnostik, diese Verbindungen enthaltende diagnostische Mittel, ihre Verwendung und Verfahren zu deren Herstellung
DE3889400T2 (de) Verwendung von Adsorptionsmittel und von Vorrichtung zur Trennung von Autoantikörper.
WO2008089756A2 (fr) Procédé de détection d'anticorps dans des liquides corporels par une réaction immunitaire avec la glycoprotéine 2 (gp2) provenant de grains de zymogène du pancréas pour diagnostiquer des maladies intestinales inflammatoires et la pancréatite chronique
WO1996004015A1 (fr) Preparations de microparticules pour l'elimination de substances dissoutes dans le sang
EP0013930A1 (fr) Immunogène, anticorps contre l'hormone thymique, hormone thymique marquée et procédé de détermination de cette hormone thymique
DE19715504A1 (de) PMMA-Membranen mit Polyethylenglykol-gekoppelten Wirksubstanzen
DE10117043A1 (de) Verfahren zur Eliminierung von potentiell toxischen und/oder schädlichen Stoffen
DE2732437C3 (de) Wasserunlösliches Haptoglobinpräparat und Verfahren zu seiner Herstellung
EP1570272A2 (fr) Identification d'autoanticorps agonistes
CH636449A5 (de) Verfahren zur gewinnung eines neuen, spezifischen alpha-l-antikoerpers.
Josephson The mechanism of the excretion of renal contrast substances
DE3879220T2 (de) Verminderung des gehaltes an lipoproteine mit geringer dichte in biologischen flüssigkeiten.
Terman et al. Specific extraction of antigen in vivo by extracorporeal circulation over antibody immobilized in collodion-charcoal
Hill et al. The absorption, distribution and excretion of 3H-chlorambucil in rats bearing the Yoshida ascites sarcoma
Kijlstra et al. Clearance and glomerular localization of preformed DNP anti‐DNP immune complexes

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA CN HU JP KR NO NZ US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

CFP Corrected version of a pamphlet front page
CR1 Correction of entry in section i

Free format text: PAT.BUL.08/96 UNDER INID (51) "IPC" DELETE "A61K 51/10"

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载